Cross‐Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities

Abstract

The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological “read‐across” approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher‐throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real‐world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2023;00:1–13. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Pharmaceuticals and Personal Care Products in the Environment: What Progress Has Been Made in Addressing the Big Research Questions?

“…On the effects side, approaches for extrapolating from molecular-level interactions to higher levels of organization need to become more quantitative, including broader taxonomic domains of applicability (Brooks et al, 2024); and more focus needs to be placed on the functional endpoints that really matter for pollution prevention and the protection of biodiversity and ecosystem services (Brooks et al, 2024;Margiotta-Casaluci et al, 2024). Work on mixtures needs to move away from considering…”

“…Significant progress has been made in the development of methods to extrapolate from effects of PPCPs in humans to effects in the natural environment. For pharmaceuticals, we have now moved from the evaluation of single-drug targets in organisms to an understanding of the conservation of all know drug targets in a wide range of species (Margiotta-Casaluci et al, 2024). Alongside this, there have been major advances in the development of adverse outcome pathways (AOPs) for PPCPs from different molecular initiation events, providing us with a much stronger foundation for extrapolating molecularlevel effects to effects on whole organisms (Brooks et al, 2024;Margiotta-Casaluci et al, 2024).…”

“…For pharmaceuticals, we have now moved from the evaluation of single-drug targets in organisms to an understanding of the conservation of all know drug targets in a wide range of species (Margiotta-Casaluci et al, 2024). Alongside this, there have been major advances in the development of adverse outcome pathways (AOPs) for PPCPs from different molecular initiation events, providing us with a much stronger foundation for extrapolating molecularlevel effects to effects on whole organisms (Brooks et al, 2024;Margiotta-Casaluci et al, 2024). The experimental effects testing area has seen the development of a range of new approach methodologies aimed at reducing the use of wholeanimal tests, including approaches for bioaccumulation, weight-of-evidence approaches, and omics-based applications (Langan et al, 2024).…”

“…Significant developments in methodologies for effects-directed analyses, including increasing access to high-resolution mass spectrometry for nontargeted analysis, means that we are now much better placed to identify drivers of toxicity in complex and undefined mixtures (Kidd et al, 2024). Increasing availability of openly available software systems, such as ECODrug, SeqAPASS, MAPPFAST, AOPwiki, and sources of toxicity ecotoxicity data (e.g., REACH dossiers, ToxCast), means that the research community is much better placed to understand the effects of PPCPs on aquatic and terrestrial organisms (Ankley et al, 2024;Margiotta-Casaluci et al, 2024) and to advance the precision of environmental assessments (Brooks et al, 2024).…”

Environmental Risks of Pharmaceutical Mixtures in Aquatic Ecosystems: Reflections on a Decade of Research

“…Closing this gap means that we need to continue collecting ecotoxicity data on APIs and to mandate open ecotoxicological data from, for example, pharmaceutical manufacturers, for both new and existing APIs. In addition, promising and valuable tools now exist for addressing data gaps across the entire tree of life and include "read-across" approaches such as ECOdrug (Verbruggen et al, 2018) and Sequence Alignment to Predict Across Species Susceptibility (LaLone et al, 2016) that extrapolate mammalian toxicity data to predict toxicity in wildlife organisms (for the state of the art in cross-species extrapolation, see Margiotta-Casaluci et al, 2024). Such predictive data will especially help to identify where to focus our experimental efforts (see also Mo et al, 2024).…”